Methods, systems, and apparatuses for managing temperatures induced by alternating fields

ABSTRACT

Methods, systems, and apparatuses are described for managing temperatures induces my alternating electric fields by selectively activating/deactivating electrodes of a pair of transducer arrays according to defined parameters.

CROSS-REFERENCE TO RELATED PATENT APPLICATION

This application claims priority to U.S. Provisional Application No.62/955,747 filed Dec. 31, 2019, which is herein incorporated byreference in its entirety.

BACKGROUND

Tumor Treating Fields, or TTFields, are low intensity (e.g., 1-3 V/cm)alternating electric fields within the intermediate frequency range(100-300 kHz). This non-invasive treatment targets solid tumors and isdescribed in U.S. Pat. No. 7,565,205, which is incorporated herein byreference in its entirety. TTFields disrupt cell division throughphysical interactions with key molecules during mitosis. TTFieldstherapy is an approved mono-treatment for recurrent glioblastoma andapproved combination therapy with chemotherapy for newly diagnosedpatients. These electric fields are induced non-invasively by transducerarrays (e.g., arrays of electrodes) placed directly on the patient'sscalp. TTFields also appear to be beneficial for treating tumors inother parts of the body. Disparities in tissue types and geometries mayreduce the efficacy of alternating electric fields when applied to atarget region. Also, the alternating electric fields applied bytransducer arrays may produce heat. The heat generated by electrodes ofa transducer array may cause patient discomfort at a tissue-transducerinterface, such as on the surface of the skin.

SUMMARY

Described are methods comprising causing cyclical application of a firstelectric field via a first transducer array in a first direction and asecond electric field via a second transducer array in a seconddirection, opposite the first direction, wherein the first transducerarray comprises a first plurality of electrodes and the secondtransducer array comprises a second plurality of electrodes, and duringthe cyclical application, deactivating, based on a temperatureassociated with the one or more electrodes of the first plurality ofelectrodes or one or more electrodes of the second plurality ofelectrodes satisfying a threshold, the one or more electrodes of thefirst plurality of electrodes or the one or more electrodes of thesecond plurality of electrodes, and activating, based on a temperatureassociated with the deactivated one or more electrodes of the firstplurality of electrodes or the deactivated one or more electrodes of thesecond plurality of electrodes no longer satisfying the threshold, thedeactivated one or more electrodes of the first plurality of electrodesor the deactivated one or more electrodes of the second plurality ofelectrodes.

Also described are methods comprising causing cyclical application of afirst electric field via a first transducer array in a first directionand a second electric field via a second transducer array in a seconddirection, opposite the first direction, to a region of interest,wherein the first transducer array comprises a first plurality ofelectrodes and the second transducer array comprises a second pluralityof electrodes, and during the cyclical application, selectivelydeactivating, one or more electrodes of the first plurality ofelectrodes or one or more electrodes of the second plurality ofelectrodes, to adjust an angle at which the first electric field or thesecond electric field is applied to the region of interest.

Additional advantages will be set forth in part in the description whichfollows or may be learned by practice. The advantages will be realizedand attained by means of the elements and combinations particularlypointed out in the appended claims. It is to be understood that both theforegoing general description and the following detailed description areexemplary and explanatory only and are not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

To easily identify the discussion of any particular element or act, themost significant digit or digits in a reference number refer to thefigure number in which that element is first introduced.

FIG. 1 shows an example apparatus for electrotherapeutic treatment.

FIG. 2 shows an example transducer array.

FIG. 3A and FIG. 3B illustrate an example application of the apparatusfor electrotherapeutic treatment.

FIG. 4A shows transducer arrays placed on a patient's head.

FIG. 4B shows transducer arrays placed on a patient's abdomen.

FIG. 5A, the transducer arrays placed on a patient's torso.

FIG. 5B shows transducer arrays placed on a patient's pelvis

FIG. 6 is a block diagram depicting an electric field generator and apatient support system.

FIG. 7 illustrates electric field magnitude and distribution (in V/cm)shown in the coronal view from a finite element method simulation model.

FIG. 8A shows a three-dimensional array layout map 800.

FIG. 8B shows the placement of transducer arrays on the scalp of apatient.

FIG. 9A shows an axial T1 sequence slice containing a most apical image,including orbits used to measure head size.

FIG. 9B shows a coronal T1 sequence slice selecting image at the levelof ear canal used to measure head size.

FIG. 9C shows a postcontrast T1 axial image shows maximal enhancingtumor diameter used to measure tumor location.

FIG. 9D shows a postcontrast T1 coronal image shows maximal enhancingtumor diameter used to measure tumor location.

FIG. 10 is a block diagram depicting an example operating environment.

FIG. 11 shows an example method.

FIG. 12 shows an example method.

DETAILED DESCRIPTION

Before the present methods and systems are disclosed and described, itis to be understood that the methods and systems are not limited tospecific methods, specific components, or to particular implementations.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only and is not intended tobe limiting.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Ranges may be expressed herein as from “about” oneparticular value, and/or to “about” another particular value. When sucha range is expressed, another embodiment includes—from the oneparticular value and/or to the other particular value. Similarly, whenvalues are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms anotherembodiment. It will be further understood that the endpoints of each ofthe ranges are significant both in relation to the other endpoint, andindependently of the other endpoint.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not.

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other components, integers or steps.“Exemplary” means “an example of” and is not intended to convey anindication of a preferred or ideal embodiment. “Such as” is not used ina restrictive sense, but for explanatory purposes.

Disclosed are components that can be used to perform the disclosedmethods and systems. These and other components are disclosed herein,and it is understood that when combinations, subsets, interactions,groups, etc. of these components are disclosed that while specificreference of each various individual and collective combinations andpermutation of these may not be explicitly disclosed, each isspecifically contemplated and described herein, for all methods andsystems. This applies to all aspects of this application including, butnot limited to, steps in disclosed methods. Thus, if there are a varietyof additional steps that can be performed it is understood that each ofthese additional steps can be performed with any specific embodiment orcombination of embodiments of the disclosed methods.

The present methods and systems may be understood more readily byreference to the following detailed description of preferred embodimentsand the examples included therein and to the Figures and their previousand following description.

As will be appreciated by one skilled in the art, the methods andsystems may take the form of an entirely hardware embodiment, anentirely software embodiment, or an embodiment combining software andhardware aspects. Furthermore, the methods and systems may take the formof a computer program product on a computer-readable storage mediumhaving computer-readable program instructions (e.g., computer software)embodied in the storage medium. More particularly, the present methodsand systems may take the form of web-implemented computer software. Anysuitable computer-readable storage medium may be utilized including harddisks, CD-ROMs, optical storage devices, or magnetic storage devices.

Embodiments of the methods and systems are described below withreference to block diagrams and flowchart illustrations of methods,systems, apparatuses, and computer program products. It will beunderstood that each block of the block diagrams and flowchartillustrations, and combinations of blocks in the block diagrams andflowchart illustrations, respectively, can be implemented by computerprogram instructions. These computer program instructions may be loadedonto a general-purpose computer, special purpose computer, or otherprogrammable data processing apparatus to produce a machine, such thatthe instructions which execute on the computer or other programmabledata processing apparatus create a means for implementing the functionsspecified in the flowchart block or blocks.

These computer program instructions may also be stored in acomputer-readable memory that can direct a computer or otherprogrammable data processing apparatus to function in a particularmanner, such that the instructions stored in the computer-readablememory produce an article of manufacture including computer-readableinstructions for implementing the function specified in the flowchartblock or blocks. The computer program instructions may also be loadedonto a computer or other programmable data processing apparatus to causea series of operational steps to be performed on the computer or otherprogrammable apparatus to produce a computer-implemented process suchthat the instructions that execute on the computer or other programmableapparatus provide steps for implementing the functions specified in theflowchart block or blocks.

Accordingly, blocks of the block diagrams and flowchart illustrationssupport combinations of means for performing the specified functions,combinations of steps for performing the specified functions and programinstruction means for performing the specified functions. It will alsobe understood that each block of the block diagrams and flowchartillustrations, and combinations of blocks in the block diagrams andflowchart illustrations, can be implemented by special purposehardware-based computer systems that perform the specified functions orsteps, or combinations of special purpose hardware and computerinstructions.

TTFields, also referred to herein as alternating electric fields, areestablished as an anti-mitotic cancer treatment modality because theyinterfere with proper microtubule assembly during metaphase andeventually destroy the cells during telophase and cytokinesis. Theefficacy increases with increasing field strength and the optimalfrequency are cancer cell line dependent with 200 kHz being thefrequency for which inhibition of glioma cell growth caused by TTFieldsis highest. For cancer treatment, non-invasive devices were developedwith capacitively coupled transducers that are placed directly at theskin region close to the tumor, for example, for patients withGlioblastoma Multiforme (GBM), the most common primary, malignant braintumor in humans.

Because the effect of TTFields is directional with cells dividingparallel to the field affected more than cells dividing in otherdirections, and because cells divide in all directions, TTFields aretypically delivered through two pairs of transducer arrays that generateperpendicular fields within the treated tumor. More specifically, onepair of transducer arrays may be located to the left and right (LR) ofthe tumor, and the other pair of transducer arrays may be locatedanterior and posterior (AP) to the tumor. Cycling the field betweenthese two directions (e.g., LR and AP) ensures that a maximal range ofcell orientations is targeted. Other positions of transducer arrays arecontemplated beyond perpendicular fields. In an embodiment, asymmetricpositioning of three transducer arrays is contemplated wherein one pairof the three transducer arrays may deliver alternating electric fieldsand then another pair of the three transducer arrays may deliver thealternating electric fields, and the remaining pair of the threetransducer arrays may deliver the alternating electric fields.

In-vivo and in-vitro studies show that the efficacy of TTFields therapyincreases as the intensity of the electric field increases. Therefore,optimizing array placement on the patient's scalp to increase theintensity in the diseased region of the brain is standard practice forthe Optune system. Array placement optimization may be performed by“rule of thumb” (e.g., placing the arrays on the scalp as close to thetumor as possible), measurements describing the geometry of thepatient's head, tumor dimensions, and/or tumor location. Measurementsused as input may be derived from imaging data. Imaging data is intendedto include any type of visual data, such as for example, single-photonemission computed tomography (SPECT) image data, x-ray computedtomography (x-ray CT) data, magnetic resonance imaging (MRI) data,positron emission tomography (PET) data, data that can be captured by anoptical instrument (e.g., a photographic camera, a charge-coupled device(CCD) camera, an infrared camera, etc.), and the like. In certainimplementations, image data may include 3D data obtained from orgenerated by a 3D scanner (e.g., point cloud data). Optimization canrely on an understanding of how the electric field distributes withinthe head as a function of the positions of the array and, in someaspects, take account for variations in the electrical propertydistributions within the heads of different patients.

FIG. 1 shows an example apparatus 100 for electrotherapeutic treatment.Generally, the apparatus 100 may be a portable, battery or power supplyoperated device which produces alternating electric fields within thebody by means of non-invasive surface transducer arrays. The apparatus100 may comprise an electric field generator 102 and one or moretransducer arrays 104. The apparatus 100 may be configured to generatetumor treatment fields (TTFields) (e.g., at 150 kHz) via the electricfield generator 102 and deliver the TTFields to an area of the bodythrough the one or more transducer arrays 104. The electric fieldgenerator 102 may be a battery and/or power supply operated device. Inan embodiment, the one or more transducer arrays 104 are uniformlyshaped. In an embodiment, the one or more transducer arrays 104 are notuniformly shaped.

The electric field generator 102 may comprise a processor 106 incommunication with a signal generator 108. The electric field generator102 may comprise control software 110 configured for controlling theperformance of the processor 106 and the signal generator 108.

The signal generator 108 may generate one or more electric signals inthe shape of waveforms or trains of pulses. The signal generator 108 maybe configured to generate an alternating voltage waveform at frequenciesin the range from about 50 kHz to about 500 kHz (preferably from about100 kHz to about 300 kHz) (e.g., the TTFields). The voltages are suchthat the electric field intensity in tissue to be treated is in therange of about 0.1 V/cm to about 10 V/cm.

One or more outputs 114 of the electric field generator 102 may becoupled to one or more conductive leads 112 that are attached at one endthereof to the signal generator 108. The opposite ends of the conductiveleads 112 are connected to the one or more transducer arrays 104 thatare activated by the electric signals (e.g., waveforms). The conductiveleads 112 may comprise standard isolated conductors with a flexiblemetal shield and can grounded to prevent the spread of the electricfield generated by the conductive leads 112. The one or more outputs 114may be operated sequentially. Output parameters of the signal generator108 may comprise, for example, an intensity of the field, a frequency ofthe waves (e.g., treatment frequency), and a maximum allowabletemperature of the one or more transducer arrays 104. The outputparameters may be set and/or determined by the control software 110 inconjunction with the processor 106. After determining a desired (e.g.,optimal) treatment frequency, the control software 110 may cause theprocessor 106 to send a control signal to the signal generator 108 thatcauses the signal generator 108 to output the desired treatmentfrequency to the one or more transducer arrays 104.

The one or more transducer arrays 104 may be configured in a variety ofshapes and positions to generate an electric field of the desiredconfiguration, direction, and intensity at a target volume to focustreatment. The one or more transducer arrays 104 may be configured todeliver two perpendicular field directions through a volume of interest.

The one or more transducer arrays 104 arrays may comprise one or moreelectrodes 116. The one or more electrodes 116 may be made from anymaterial with a high dielectric constant. The one or more electrodes 116may comprise, for example, one or more insulated ceramic discs. Theelectrodes 116 may be biocompatible and coupled to a flexible circuitboard 118. The electrodes 116 may be configured to not come into directcontact with the skin as the electrodes 116 are separated from the skinby a layer of conductive hydrogel (not shown) (similar to that found onelectrocardiogram pads).

The electrodes 116, the hydrogel, and the flexible circuit board 118 maybe attached to a hypoallergenic medical adhesive bandage 120 to keep theone or more transducer arrays 104 in place on the body and in continuousdirect contact with the skin. Each transducer array 104 may comprise oneor more thermistors (not shown), for example, 8 thermistors, (accuracy±1° C.) to measure skin temperature beneath the transducer arrays 104.The thermistors may be configured to measure skin temperatureperiodically, for example, every second. The thermistors may be read bythe control software 110 while the TTFields are not being delivered toavoid any interference with the temperature measurements.

If the temperature measured is below a pre-set maximum temperature(Tmax), for example, 38.5-40.0° C.±0.3° C., between two subsequentmeasures, the control software 110 can increase current until thecurrent reaches maximal treatment current (for example, 4 Ampspeak-to-peak). If the temperature reaches Tmax+0.3° C. and continues torise, the control software 110 can lower the current. If the temperaturerises to 41° C., the control software 110 can shut off the TTFieldstherapy and an overheating alarm can be triggered.

The one or more transducer arrays 104 may vary in size and may comprisevarying numbers of electrodes 116, based on patient body sizes and/ordifferent therapeutic treatments. For example, in the context of thechest of a patient, small transducer arrays may comprise 13 electrodeseach, and large transducer arrays may comprise 20 electrodes each, withthe electrodes serially interconnected in each array. For example, asshown in FIG. 2, in the context of the head of a patient, eachtransducer array may comprise 9 electrodes each, with the electrodesserially interconnected in each array.

Alternative constructions for the one or more transducer arrays 104 arecontemplated and may also be used, including, for example, transducerarrays that use ceramic elements that are not disc-shaped, andtransducer arrays that use non-ceramic dielectric materials positionedover a plurality of flat conductors. Examples of the latter includepolymer films disposed over pads on a printed circuit board or over flatpieces of metal. Transducer arrays that use electrode elements that arenot capacitively coupled may also be used. In this situation, eachelement of the transducer array would be implemented using a region of aconductive material that is configured for placement against asubject/patient's body, with no insulating dielectric layer disposedbetween the conductive elements and the body. Other alternativeconstructions for implementing the transducer arrays may also be used.Any transducer array (or similar device/component) configuration,arrangement, type, and/or the like may be used for the methods andsystems described herein as long as the transducer array (or similardevice/component) configuration, arrangement, type, and/or the like is(a) capable of delivering TTFields to a subject/patient's body and (b)and may be positioned arranged, and/or placed on a portion of apatient/subject's body as described herein.

Status of the apparatus 100 and monitored parameters may be stored amemory (not shown) and can be transferred to a computing device over awired or wireless connection. The apparatus 100 may comprise a display(not shown) for displaying visual indicators, such as, power on,treatment on, alarms, and low battery.

FIG. 3A and FIG. 3B illustrate an example application of the apparatus100. A transducer array 104 a and a transducer array 104 b are shown,each incorporated into a hypoallergenic medical adhesive bandage 120 aand 120 b, respectively. The hypoallergenic medical adhesive bandages120 a and 120 b are applied to skin surface 302. A tumor 304 is locatedbelow the skin surface 302 and bone tissue 306 and is located withinbrain tissue 308. The electric field generator 102 causes the transducerarray 104 a and the transducer array 104 b to generate alternatingelectric fields 310 within the brain tissue 308 that disrupt rapid celldivision exhibited by cancer cells of the tumor 304. The alternatingelectric fields 310 have been shown in non-clinical experiments toarrest the proliferation of tumor cells and/or to destroy them. Use ofthe alternating electric fields 310 takes advantage of the specialcharacteristics, geometrical shape, and rate of dividing cancer cells,which make them susceptible to the effects of the alternating electricfields 310. The alternating electric fields 310 alter their polarity atan intermediate frequency (on the order of 100-300 kHz). The frequencyused for a particular treatment may be specific to the cell type beingtreated (e.g., 150 kHz for MPM). The alternating electric fields 310have been shown to disrupt mitotic spindle microtubule assembly and tolead to dielectrophoretic dislocation of intracellular macromoleculesand organelles during cytokinesis. These processes lead to the physicaldisruption of the cell membrane and programmed cell death (apoptosis).

Because the effect of the alternating electric fields 310 is directionalwith cells dividing parallel to the field affected more than cellsdividing in other directions, and because cells divide in alldirections, alternating electric fields 310 may be delivered through twopairs of transducer arrays 104 that generate perpendicular fields withinthe treated tumor. Theory and modeling predict that the directional,tumor-killing effect of the alternating electric fields 310 is due totheir disruption of cellular structures whose spatial orientationrenders them maximally susceptible to the disruptive effect when theyare parallel to the alternating electric fields 310. Thus, theory andmodeling predict that changing the direction of the alternating electricfields 310 multiple times in specific directions will have the maximaldisruptive effect on the cellular structures, with each added change ofdirection reducing the variance of electric field strength received bythe cellular structure. Thus, if the mean field strength at the cell iswhat is required to kill the cell if all cellular structures werealigned with the field (e.g., ‘efficacious’ field strength), withoutchanging the field direction, some structures see less than efficaciousfield strength while some see more than efficacious field strength,while with changes of direction, fewer structures see sub-efficaciousfield strength with the harmless trade-off that fewer structures atsupra-efficacious see reduced field strength that is stillsupra-efficacious. More specifically, one pair of transducer arrays 104may be located to the left and right (LR) of the tumor, and the otherpair of transducer arrays 104 may be located anterior and posterior (AP)to the tumor. Cycling the alternating electric fields 310 between thesetwo directions (e.g., LR and AP) ensures that a larger range of cellorientations is targeted than with one direction only. In an embodiment,the alternating electric fields 310 may be delivered according to asymmetric setup of transducer arrays 104 (e.g., four total transducerarrays 104, two matched pairs). In another embodiment, the alternatingelectric fields 310 may be delivered according to an asymmetric setup oftransducer arrays 104 (e.g., three total transducer arrays 104). Anasymmetric setup of transducer arrays 104 may engage two of the threetransducer arrays 104 to deliver the alternating electric fields 310 andthen switch to another two of the three transducer arrays 104 to deliverthe alternating electric fields 310, and the like. In an embodiment,subsets of transducer arrays 104 may be used to achieve more changes ofdirection of the alternating electric fields 310 than are possible byusing the full transducer array 104 in each location.

In other embodiments, the changes of direction of electric fields 310via transducer arrays, or their subset transducers, would attempt toattain the following angles for each number of directions: 90 degrees intwo dimensions for two directions, 90 degrees in three directions, allorthogonal to each other, in three dimensions, and the dihedral angle ofthe tetrahedron (˜70.53 degrees) in three dimensions with four changes.

Electric fields (e.g., the alternating electric fields 310, etc.) mayheat tissue (e.g., the skin surface 302, etc.) under and/or neartransducers. Also, because different regions of a patient's body arecomposed of different geometric shapes and electrical properties, theconductivity of tissues may vary according to orientation to an imposedfield causing inhomogeneous concentrations of field strength. Further,an electric field may be reduced in strength and efficacy (e.g.,shunted, etc.) due to the presence of conductive body fluids such ascerebrospinal fluid (CSF). In some instances, the apparatus 100 may beconfigured to reduce and/or eliminate instances of tissue heating at thetranducer-tissue interface. For example, the apparatus 100 may beconfigured to cyclically activate and deactivate electrodes of atransducer array to alter the direction and/or duration of an electricfield (e.g., to impose alignment or orthogonality with cell axes withina region- or interest (ROI)) and reduce high-temperature points at thetransducer-skin interface by allowing deactivated electrodes to cool tothe desired temperature, such as a threshold temperature. An optimalinterval at which to alter field direction may be determined by analysisof a tissue model that includes tissue/information from a plurality ofpatients. Optimal parameters for field strength, frequency, and durationmay be determined according to variations in the geometry of varioustissue samples the electric field generator 102 may be configured to‘sweep’ through various parameter ranges and determine the effect of theparameters on an efficacious dose at a target ROI (e.g., tumor, etc.).When a specific tissue geometry of a patient is unknown and/or tissuegeometry is significantly inhomogeneous due to geometry and tissueproperties, a random selection of angles at optimal duty cyclesdetermined by the electric field generator 102, such as a 50 ms dutycycle and/or a or temperature-limited duty cycle, may optimize theaverage therapeutic dose delivered to a target ROI (e.g., tumor, etc.).When a tumor location and/or tissue inhomogeneity of a patient isdetermined, the electric field generator 102 may activate/deactivatecathode and anode combinations of the transducer arrays 104 based on thelocation/placement of the transducer arrays 104 and relative orientationto the geometric center of the target ROI.

In some instances, the apparatus 100 may include one or more thermistorsthat indicate the temperature state of the one or more electrodes 116 ofthe transducer arrays 104. A feedback loop may be established betweenthe one or more thermistors and the processor 106 and/or the controlsoftware 110. The electric field generator 102, based on the feedbackloop, may be configured to optimally maximize current and/or voltagedelivered to the transducer arrays 104 by cycling patterns of electricfield amplitude changes at fixed or variable cycle lengths. For example,the electric field generator 102 may cyclically and simultaneouslydeactivate (e.g., turn off amplitude, etc.) one or more electrodes ofthe transducer arrays 104 with the highest sensed temperatures andactivate (e.g., turn on amplitude, etc.) one or more electrodes of thetransducer arrays 104 according to a function of electrode temperatureand an available selection of angles between electrodes of thetransducer arrays 104. In some instances, the function of electrodetemperature and inter-electrode angle may be a weighted product oftemperature multiplied by a function of the angle between the differencein temperature between two electrodes and an angle between lines drawnfrom centers of the two electrodes to the geometric center of a targetROI. In some instances, electrodes of the transducer arrays 104 may beactivated for durations of decreasing increments such that thetemperature of the activated electrodes approaches an asymptotic limit.The decreasing increments of the durations may be based on a differencebetween the asymptotic limit and the temperature of the activatedelectrodes at a given point in time.

In some instances, electrodes of the transducer arrays 104 may beactivated for durations that are limited by the temperature of theelectrodes approaching an asymptotic limit according to the followingfunction:

Temp(t)=Temp(t−1)*Temp_(Max)−Exp[−Temp(t−1)/Temp_(max)]),  Function 1:

where Temp_(Max) is a temperature limit set for a transducer region andt is time.

In some instances, electrodes of the transducer arrays 104 may beactivated for durations that are limited by the temperature of theelectrodes approaching an asymptotic limit according to the followingfunction:

Temp(t)=Temp(t−1)*Temp_(Max)−Exp[−t/τ _(tissue)]),  Function 2:

where Temp_(Max) is a temperature limit set for a transducer region, tis time, and τ_(tissue) is a time constant for a tissue based onempirical or theoretical estimates of its heat diffusion rate.

In-vivo and in-vitro studies show that the efficacy of TTFields therapyincreases as the intensity of the electric field increases. The methods,systems, and apparatuses described are configured for optimizing arrayplacement on the patient's scalp to increase the intensity in thediseased region of the brain.

As shown in FIG. 4A, the transducer arrays 104 may be placed on apatient's head. As shown in FIG. 4B, the transducer arrays 104 may beplaced on a patient's abdomen. As shown in FIG. 5A, the transducerarrays 104 may be placed on a patient's torso. As shown in FIG. 5B, thetransducer arrays 104 may be placed on a patient's pelvis. Placement ofthe transducer arrays 104 on other portions of a patient's body (e.g.,arm, leg, etc.) are specifically contemplated.

FIG. 6 is a block diagram depicting non-limiting examples of a system600 comprising a patient support system 602. The patient support system602 can comprise one or multiple computers configured to operate and/orstore an electric field generator (EFG) configuration application 606, apatient modeling application 608, and/or imaging data 610. The patientsupport system 602 can comprise, for example, a computing device. Thepatient support system 602 can comprise, for example, a laptop computer,a desktop computer, a mobile phone (e.g., a smartphone), a tablet, andthe like.

The patient modeling application 608 may be configured to generate athree dimensional model of a portion of a body of a patient (e.g., apatient model) according to the imaging data 610. The imaging data 610may comprise any type of visual data, for example, single-photonemission computed tomography (SPECT) image data, x-ray computedtomography (x-ray CT) data, magnetic resonance imaging (MRI) data,positron emission tomography (PET) data, data that can be captured by anoptical instrument (e.g., a photographic camera, a charge-coupled device(CCD) camera, an infrared camera, etc.), and the like. In certainimplementations, image data may include 3D data obtained from orgenerated by a 3D scanner (e.g., point cloud data). The patient modelingapplication 608 may also be configured to generate a three-dimensionalarray layout map based on the patient model and one or more electricfield simulations.

To properly optimize array placement on a portion of a patient's body,the imaging data 610, such as MRI imaging data, may be analyzed by thepatient modeling application 608 to identify a region of interest thatcomprises a tumor. In the context of a patient's head, to characterizehow electric fields behave and distribute within the human head,modeling frameworks based on anatomical head models using Finite ElementMethod (FEM) simulations may be used. These simulations yield realistichead models based on magnetic resonance imaging (MRI) measurements andcompartmentalize tissue types such as skull, white matter, gray matter,and cerebrospinal fluid (CSF) within the head. Each tissue type may beassigned dielectric properties for relative conductivity andpermittivity, and simulations may be run whereby different transducerarray configurations are applied to the surface of the model tounderstand how an externally applied electric field, of presetfrequency, will distribute throughout any portion of a patient's body,for example, the brain. The results of these simulations, employingpaired array configurations, a constant current, and a preset frequencyof 200 kHz, have demonstrated that electric field distributions arerelatively non-uniform throughout the brain and that electric fieldintensities exceeding 1 V/cm are generated in most tissue compartmentsexcept CSF. These results are obtained assuming total currents with apeak-to-peak value of 1800 milliamperes (mA) at the transducerarray-scalp interface. This threshold of electric field intensity issufficient to arrest cellular proliferation in glioblastoma cell lines.Additionally, by manipulating the configuration of paired transducerarrays, it is possible to achieve an almost tripling of electric fieldintensity to a particular region of the brain as shown in FIG. 7. FIG. 7illustrates electric field magnitude and distribution (in V/cm) shown inthe coronal view from a finite element method simulation model. Thissimulation employs a left-right paired transducer array configuration.

In an aspect, the patient modeling application 608 may be configured todetermine a desired (e.g., optimal) transducer array layout for apatient based on the location and extent of the tumor. For example,initial morphometric head size measurements may be determined from theT1 sequences of a brain MRI, using axial and coronal views. Postcontrastaxial and coronal MRI slices may be selected to demonstrate the maximaldiameter of enhancing lesions. Employing measures of head size anddistances from predetermined fiducial markers to tumor margins, varyingpermutations, and combinations of paired array layouts may be assessedto generate the configuration which delivers maximal electric fieldintensity to the tumor site. As shown in FIG. 8A, the output may be athree-dimensional array layout map 800. The three-dimensional arraylayout map 800 may be used by the patient and/or caregiver in arrangingarrays on the scalp during the normal course of TTFields therapy asshown in FIG. 8B.

In an aspect, the patient modeling application 608 can be configured todetermine the three-dimensional array layout map for a patient. MRImeasurements of the portion of the patient that is to receive thetransducer arrays may be determined. By way of example, the MRImeasurements may be received via a standard Digital Imaging andCommunications in Medicine (DICOM) viewer. MRI measurement determinationmay be performed automatically, for example by way of artificialintelligence techniques, or may be performed manually, for example byway of a physician.

Manual MRI measurement determination may comprise receiving and/orproviding MRI data via a DICOM viewer. The MRI data may comprise scansof the portion of the patient that contains a tumor. By way of example,in the context of the head of a patient, the MRI data may comprise scansof the head that comprise one or more of a right frontotemporal tumor, aright parieto-temporal tumor, a left frontotemporal tumor, a leftparieto-occipital tumor, and/or a multi-focal midline tumor. FIG. 9A,FIG. 9B, FIG. 9C, and FIG. 9D show example MRI data showing scans of thehead of a patient. FIG. 9A shows an axial T1 sequence slice containingthe most apical image, including orbits used to measure head size. FIG.9B shows a coronal T1 sequence slice selecting image at the level of earcanal used to measure head size. FIG. 9C shows a postcontrast T1 axialimage shows maximal enhancing tumor diameter used to measure tumorlocation. FIG. 9D shows a postcontrast T1 coronal image shows maximalenhancing tumor diameter used to measure tumor location. MRImeasurements may commence from fiducial markers at the outer margin ofthe scalp and extend tangentially from a right-, anterior-, superiororigin. Morphometric head size may be estimated from the axial T1 MRIsequence selecting the most apical image which still included the orbits(or the image directly above the superior edge of the orbits)

In an aspect, the MRI measurements may comprise, for example, one ormore head size measurements and/or tumor measurements. In an aspect, oneor more MRI measurements may be rounded to the nearest millimeter andmay be provided to a transducer array placement module (e.g., software)for analysis. The MRI measurements may then be used to generate thethree-dimensional array layout map (e.g., three-dimensional array layoutmap 800).

The MRI measurements may comprise one or more head size measurementssuch as: a maximal anteroposterior (A-P) head size, commencingmeasurement from the outer margin of the scalp; a maximal width of thehead perpendicular to the A-P measurement: right to left lateraldistance; and/or a distance from the far most right margin of the scalpto the anatomical midline.

The MRI measurements may comprise one or more head size measurementssuch as coronal view head size measurements. Coronal view head sizemeasurements may be obtained on the T1 MRI sequence selecting the imageat the level of the ear canal (FIG. 9B). The coronal view head sizemeasurements may comprise one or more of: a vertical measurement fromthe apex of the scalp to an orthogonal line delineating the inferiormargin of the temporal lobes; a maximal right to left lateral headwidth; and/or a distance from the far right margin of the scalp to theanatomical midline.

The MRI measurements may comprise one or more tumor measurements, suchas tumor location measurements. The tumor location measurements may bemade using T1 postcontrast MRI sequences, firstly on the axial imagedemonstrating maximal enhancing tumor diameter (FIG. 9C). The tumorlocation measurements may comprise one or more of: a maximal A-P headsize, excluding the nose; a maximal right to left lateral diameter,measured perpendicular to the A-P distance; a distance from the rightmargin of the scalp to the anatomical midline; a distance from the rightmargin of the scalp to the closest tumor margin, measured parallel tothe right-left lateral distance and perpendicular to the A-Pmeasurement; a distance from the right margin of the scalp to thefarthest tumor margin, measured parallel to the right-left lateraldistance, perpendicular to the A-P measurement; a distance from thefront of the head, measured parallel to the A-P measurement, to theclosest tumor margin; and/or a distance from the front of the head,measured parallel to the A-P measurement, to the farthest tumor margin.

The one or more tumor measurements may comprise coronal view tumormeasurements. The coronal view tumor measurements may compriseidentifying the postcontrast T1 MRI slice featuring the maximal diameterof tumor enhancement (FIG. 9D). The coronal view tumor measurements maycomprise one or more of: a maximal distance from the apex of the scalpto the inferior margin of the cerebrum. In anterior slices, this wouldbe demarcated by a horizontal line drawn at the inferior margin of thefrontal or temporal lobes, and posteriorly, it would extend to thelowest level of visible tentorium; a maximal right to left lateral headwidth; a distance from the right margin of the scalp to the anatomicalmidline; a distance from the right margin of the scalp to the closesttumor margin, measured parallel to the right-left lateral distance; adistance from the right margin of the scalp to the farthest tumormargin, measured parallel to the right-left lateral distance; a distancefrom the apex of the head to the closest tumor margin, measured parallelto the superior apex to inferior cerebrum line; and/or a distance fromthe apex of the head to the farthest tumor margin, measured parallel tothe superior apex to inferior cerebrum line.

Other MRI measurements may be used, particularly when the tumor ispresent in another portion of the patient's body.

The MRI measurements may be used by the patient modeling application 608to generate a patient model. The patient model may then be used todetermine the three-dimensional array layout map (e.g.,three-dimensional array layout map 800). Continuing the example of atumor within the head of a patient, a healthy head model may begenerated which serves as a deformable template from which patientmodels can be created. When creating a patient model, the tumor may besegmented from the patient's MRI data (e.g., the one or more MRImeasurements). Segmenting the MRI data identifies the tissue type ineach voxel, and electric properties may be assigned to each tissue typebased on empirical data. Table 1 shows standard electrical properties oftissues that may be used in simulations. The region of the tumor in thepatient MRI data may be masked, and non-rigid registration algorithmsmay be used to register the remaining regions of the patient head on toa 3D discrete image representing the deformable template of the healthyhead model. This process yields a non-rigid transformation that maps thehealthy portion of the patient's head in to the template space, as wellas the inverse transformation that maps the template in to the patientspace. The inverse transformation is applied to the 3D deformabletemplate to yield an approximation of the patient head in the absence ofa tumor. Finally, the tumor (referred to as a region-of-interest (ROI))is planted back into the deformed template to yield the full patientmodel. The patient model may be a digital representation in threedimensional space of the portion of the patient's body, includinginternal structures, such as tissues, organs, tumors, etc.

TABLE 1 Tissue Type Conductivity, S/m Relative Permittivity Scalp 0.35000 Skull 0.08 200 Cerebrospinal fluid 1.79 110 Gray matter 0.25 3000White matter 0.12 2000 Enhancing tumor 0.24 2000 Enhancing nontumor 0.361170 Resection cavity 1.79 110 Necrotic tumor 1 110 Hematoma 0.3 2000Ischemia 0.18 2500 Atrophy 1 110 Air 0 0

Delivery of TTFields may then be simulated by the patient modelingapplication 608 using the patient model. Simulated electric fielddistributions, dosimetry, and simulation-based analysis are described inU.S. Patent Publication No. 20190117956 A1 and Publication “Correlationof Tumor treating Fields Dosimetry to Survival Outcomes in NewlyDiagnosed Glioblastoma: A Large-Scale Numerical Simulation-basedAnalysis of Data from the Phase 3 EF-14 randomized Trial” by Ballo, etal. (2019) which are incorporated herein by reference in their entirety.

To ensure systematic positioning of the transducer arrays relative tothe tumor location, a reference coordinate system may be defined. Forexample, a transversal plane may initially be defined by conventional LRand AP positioning of the transducer arrays. The left-right directionmay be defined as the x-axis, the AP direction may be defined as they-axis, and the craniocaudal direction normal to the XY-plane may bedefined as the Z-axis.

After defining the coordinate system, transducer arrays may be virtuallyplaced on the patient model with their centers and longitudinal axes inthe XY-plane. A pair of transducer arrays may be systematically rotatedaround the z-axis of the head model, e.g., in the XY-plane, from 0 to180 degrees, thereby covering the entire circumference of the head (bysymmetry). The rotation interval may be, for example, 15 degrees,corresponding to approximately 2 cm translations, giving a total oftwelve different positions in the range of 180 degrees. Other rotationintervals are contemplated. Electric field distribution calculations maybe performed for each transducer array position relative to tumorcoordinates.

Electric field distribution in the patient model may be determined bythe patient modeling application 608 using a finite element (FE)approximation of electrical potential. In general, the quantitiesdefining a time-varying electromagnetic field are given by the complexMaxwell equations. However, in biological tissues and at the low tointermediate frequency of TTFields (f=200 kHz), the electromagneticwavelength is much larger than the size of the head and the electricpermittivity c is negligible compared to the real-valued electricconductivity σ, e.g., where ω=2πf is the angular frequency. This impliesthat the electromagnetic propagation effects and capacitive effects inthe tissue are negligible, so the scalar electric potential may be wellapproximated by the static Laplace equation ∇·(σ∇ϕ)=0, with appropriateboundary conditions at the electrodes and skin. Thus, the compleximpedance is treated as resistive (e.g., reactance is negligible) andcurrents flowing within the volume conductor are, therefore, mainly free(Ohmic) currents. The FE approximation of Laplace's equation wascalculated using the SimNIBS software (simnibs.org). Computations werebased on the Galerkin method and the residuals for the conjugategradient solver were required to be <1E-9. Dirichlet boundary conditionswere used with the electric potential was set to (arbitrarily chosen)fixed values at each set of electrode arrays. The electric (vector)field was calculated as the numerical gradient of the electric potentialand the current density (vector field) was computed from the electricfield using Ohm's law. The potential difference of the electric fieldvalues and the current densities were linearly rescaled to ensure atotal peak-to-peak amplitude for each array pair of 1.8 A, calculated asthe (numerical) surface integral of the normal current densitycomponents over all triangular surface elements on the active electrodediscs. This corresponds to the current level used for clinical TTFieldstherapy by the Optune® device. The “dose” of TTFields was calculated asthe intensity (L2 norm) of the field vectors. The modeled current isassumed to be provided by two separate and sequentially active sourceseach connected to a pair of 3×3 transducer arrays. The left andposterior arrays may be defined to be sources in the simulations, whilethe right and anterior arrays were the corresponding sinks,respectively. However, as TTFields employ alternating fields, thischoice is arbitrary and does not influence the results.

An average electric field strength generated by transducer arrays placedat multiple locations on the patient may be determined by the patientmodeling application 608 for one or more tissue types. In an aspect, thetransducer array position that corresponds to the highest averageelectric field strength in the tumor tissue type(s) may be selected as adesired (e.g., optimal) transducer array position for the patient. Inanother aspect, one or more candidate positions for a transducerarray(s) may be excluded as a result of a physical condition of thepatient. For example, one or more candidate positions may be excludedbased on areas of skin irritation, scars, surgical sites, discomfort,etc. Accordingly, the transducer array position that corresponds to thehighest average electric field strength in the tumor tissue type(s),after excluding one or more candidate positions, may be selected as adesired (e.g., optimal) transducer array position for the patient. Thus,a transducer array position may be selected that results in less thanthe maximum possible average electric field strength.

The patient model may be modified to include an indication of thedesired transducer array position. The resulting patient model,comprising the indication(s) of the desired transducer arrayposition(s), may be referred to as the three-dimensional array layoutmap (e.g., three-dimensional array layout map 600). Thethree-dimensional array layout map may thus comprise a digitalrepresentation, in three-dimensional space, of the portion of thepatient's body, an indication of tumor location, an indication of aposition for placement of one or more transducer arrays, combinationsthereof, and the like.

The three-dimensional array layout map may be provided to the patient ina digital form and/or a physical form. The patient, and/or a patientcaregiver, may use the three-dimensional array layout map to affix oneor more transducer arrays to an associated portion of the patient's body(e.g., head).

FIG. 10 is a block diagram depicting an environment 1000 comprising anon-limiting example of the patient support system 104. In an aspect,some or all steps of any described method may be performed on acomputing device as described herein. The patient support system 104 cancomprise one or multiple computers configured to store one or more ofthe EFG configuration application 606, the patient modeling application608, the imaging data 610, and the like.

The patient support system 104 can be a digital computer that, in termsof hardware architecture, generally includes a processor 1008, memorysystem 1010, input/output (I/O) interfaces 1012, and network interfaces1014. These components (1008, 1010, 1012, and 1014) are communicativelycoupled via a local interface 1016. The local interface 1016 can be, forexample, but not limited to, one or more buses or other wired orwireless connections, as is known in the art. The local interface 1016can have additional elements, which are omitted for simplicity, such ascontrollers, buffers (caches), drivers, repeaters, and receivers, toenable communications. Further, the local interface may include address,control, and/or data connections to enable appropriate communicationsamong the aforementioned components.

The processor 1008 can be a hardware device for executing software,particularly that stored in memory system 1010. The processor 1008 canbe any custom made or commercially available processor, a centralprocessing unit (CPU), an auxiliary processor among several processorsassociated with the patient support system 1002, a semiconductor-basedmicroprocessor (in the form of a microchip or chipset), or generally anydevice for executing software instructions. When the patient supportsystem 1002 is in operation, the processor 1008 can be configured toexecute software stored within the memory system 1010, to communicatedata to and from the memory system 1010, and to generally controloperations of the patient support system 1002 pursuant to the software.

The I/O interfaces 1012 can be used to receive user input from and/orfor providing system output to one or more devices or components. Userinput can be provided via, for example, a keyboard and/or a mouse.System output can be provided via a display device and a printer (notshown). I/O interfaces 1012 can include, for example, a serial port, aparallel port, a Small Computer System Interface (SCSI), an IRinterface, an RF interface, and/or a universal serial bus (USB)interface.

The network interface 1014 can be used to transmit and receive from thepatient support system 1002. The network interface 1014 may include, forexample, a 10BaseT Ethernet Adaptor, a 100BaseT Ethernet Adaptor, a LANPHY Ethernet Adaptor, a Token Ring Adaptor, a wireless network adapter(e.g., WiFi), or any other suitable network interface device. Thenetwork interface 1014 may include address, control, and/or dataconnections to enable appropriate communications.

The memory system 1010 can include any one or combination of volatilememory elements (e.g., random access memory (RAM, such as DRAM, SRAM,SDRAM, etc.)) and nonvolatile memory elements (e.g., ROM, hard drive,tape, CDROM, DVDROM, etc.). Moreover, the memory system 1010 mayincorporate electronic, magnetic, optical, and/or other types of storagemedia. Note that the memory system 1010 can have a distributedarchitecture, where various components are situated remote from oneanother, but can be accessed by the processor 1008.

The software in memory system 1010 may include one or more softwareprograms, each of which comprises an ordered listing of executableinstructions for implementing logical functions. In the example of FIG.10, the software in the memory system 1010 of the patient support system1002 can comprise the EFG configuration application 606, the patientmodeling application 608, the imaging data 610, and a suitable operatingsystem (O/S) 1018. The operating system 1018 essentially controls theexecution of other computer programs, and provides scheduling,input-output control, file and data management, memory management, andcommunication control and related services.

For purposes of illustration, application programs and other executableprogram components such as the operating system 1018 are illustratedherein as discrete blocks, although it is recognized that such programsand components can reside at various times in different storagecomponents of the patient support system 104. An implementation of theEFG configuration application 606, the patient modeling application 608,the imaging data 610, and/or the control software 110 can be stored onor transmitted across some form of computer readable media. Any of thedisclosed methods can be performed by computer readable instructionsembodied on computer readable media. Computer readable media can be anyavailable media that can be accessed by a computer. By way of exampleand not meant to be limiting, computer readable media can comprise“computer storage media” and “communications media.” “Computer storagemedia” can comprise volatile and non-volatile, removable andnon-removable media implemented in any methods or technology for storageof information such as computer readable instructions, data structures,program modules, or other data. Exemplary computer storage media cancomprise RAM, ROM, EEPROM, flash memory or other memory technology,CD-ROM, digital versatile disks (DVD) or other optical storage, magneticcassettes, magnetic tape, magnetic disk storage or other magneticstorage devices, or any other medium which can be used to store thedesired information and which can be accessed by a computer.

In an embodiment, illustrated in FIG. 11, one or more of the apparatus100, the patient support system 602, the patient modeling application608, and/any other device/component described herein can be configuredto perform a method 1100 comprising, at 1110, causing cyclicalapplication of a first electric field via a first transducer array in afirst direction and a second electric field via a second transducerarray in a second direction, opposite the first direction, wherein thefirst transducer array comprises a first plurality of electrodes and thesecond transducer array comprises a second plurality of electrodes.

In some instances, the first electric field and the second electricfield may be applied with a frequency between 50 and 500 kHz andelectric field strength of at least 1 V/cm to a tumor.

In some instances, the cyclical application may include applying thefirst electric field for between 20 and 500 ms in the first directionand the second electric field for between 20 and 500 ms in the seconddirection during each cycle.

The method 1100 may include, during the cyclical application, at 1120,deactivating, based on a temperature associated with the one or moreelectrodes of the first plurality of electrodes or one or moreelectrodes of the second plurality of electrodes satisfying a threshold,the one or more electrodes of the first plurality of electrodes or theone or more electrodes of the second plurality of electrodes, and at1130, activating, based on a temperature associated with the deactivatedone or more electrodes of the first plurality of electrodes or thedeactivated one or more electrodes of the second plurality of electrodesno longer satisfying the threshold, the deactivated one or moreelectrodes of the first plurality of electrodes or the deactivated oneor more electrodes of the second plurality of electrodes.

In some instances, the method 1100 may include determining that thetemperature associated with the one or more electrodes of the firstplurality of electrodes or the one or more electrodes of the secondplurality of electrodes satisfies the threshold.

In some instances, the method 1100 may include determining that thetemperature associated with the deactivated one or more electrodes ofthe first plurality of electrodes or the deactivated one or moreelectrodes of the second plurality of electrodes no longer satisfies thethreshold.

In some instances, the method 1100 may include, during the cyclicalapplication, selectively deactivating, one or more electrodes of thefirst plurality of electrodes or one or more electrodes of the secondplurality of electrodes, to adjust an angle at which the first electricfield or the second electric field is applied to the region of interest.In some instances, selectively deactivating the one or more electrodesof the first plurality of electrodes or the one or more electrodes ofthe second plurality of electrodes may be based on a random selection ofangles at an optimal duty cycle. In some instances, selectivelydeactivating the one or more electrodes of the first plurality ofelectrodes or the one or more electrodes of the second plurality ofelectrodes may be based on a random selection of angles at atemperature-limited duty cycle. In some instances, selectivelydeactivating the one or more electrodes of the first plurality ofelectrodes or the one or more electrodes of the second plurality ofelectrodes may be based on the selection of angles that are orthogonalrelative to a geometric center of the region of interest. In someinstances, selectively deactivating the one or more electrodes of thefirst plurality of electrodes or the one or more electrodes of thesecond plurality of electrodes may be based on the selection of anglesthat are orthogonal relative to pairs of cathode electrodes and anodeelectrodes that are orthogonal to each other. In some instances,selectively deactivating the one or more electrodes of the firstplurality of electrodes or the one or more electrodes of the secondplurality of electrodes may be based on the selection of angles that aremost distant from previous angles used within a current duty cycle.

In an embodiment, illustrated in FIG. 12, one or more of the apparatus100, the patient support system 602, the patient modeling application608, and/any other device/component described herein can be configuredto perform a method 1200 comprising, at 1210, causing cyclicalapplication of a first electric field via a first transducer array in afirst direction and a second electric field via a second transducerarray in a second direction, opposite the first direction, to a regionof interest, wherein the first transducer array comprises a firstplurality of electrodes and the second transducer array comprises asecond plurality of electrodes.

At 1220, during the cyclical application, selectively deactivating, oneor more electrodes of the first plurality of electrodes or one or moreelectrodes of the second plurality of electrodes, to adjust an angle atwhich the first electric field or the second electric field is appliedto the region of interest. In some instances, selectively deactivatingthe one or more electrodes of the first plurality of electrodes or theone or more electrodes of the second plurality of electrodes may bebased on a random selection of angles at an optimal duty cycle. In someinstances, selectively deactivating the one or more electrodes of thefirst plurality of electrodes or the one or more electrodes of thesecond plurality of electrodes may be based on a random selection ofangles at a temperature-limited duty cycle.

In some instances, selectively deactivating the one or more electrodesof the first plurality of electrodes or the one or more electrodes ofthe second plurality of electrodes may be based on the selection ofangles that are orthogonal relative to a geometric center of the regionof interest.

In some instances, selectively deactivating the one or more electrodesof the first plurality of electrodes or the one or more electrodes ofthe second plurality of electrodes may be based on the selection ofangles that are orthogonal relative to pairs of cathode electrodes andanode electrodes that are orthogonal to each other.

In some instances, selectively deactivating the one or more electrodesof the first plurality of electrodes or the one or more electrodes ofthe second plurality of electrodes may be based on the selection ofangles that are most distant from previous angles used within a currentduty cycle.

The method 1200 may include, during the cyclical application,deactivating, based on a temperature associated with the one or moreelectrodes of the first plurality of electrodes or the one or moreelectrodes of the second plurality of electrodes satisfying a threshold,the one or more electrodes of the first plurality of electrodes or theone or more electrodes of the second plurality of electrodes, andactivating, based on a temperature associated with the deactivated oneor more electrodes of the first plurality of electrodes or thedeactivated one or more electrodes of the second plurality of electrodesno longer satisfying the threshold, the deactivated one or moreelectrodes of the first plurality of electrodes or the deactivated oneor more electrodes of the second plurality of electrodes.

In some instances, selectively deactivating the one or more electrodesof the first plurality of electrodes or the one or more electrodes ofthe second plurality of electrodes may be based on a random selection ofangles at an optimal duty cycle and a temperature associateddeactivation state of one or more electrodes.

In some instances, selectively deactivating the one or more electrodesof the first plurality of electrodes or the one or more electrodes ofthe second plurality of electrodes may be based on a random selection ofangles at a temperature-limited duty cycle and a temperature associateddeactivation state of one or more electrodes.

In some instances, selectively deactivating the one or more electrodesof the first plurality of electrodes or the one or more electrodes ofthe second plurality of electrodes may be based on the selection ofangles that are orthogonal relative to a geometric center of the regionof interest and a temperature associated deactivation state of one ormore electrodes.

In some instances, selectively deactivating the one or more electrodesof the first plurality of electrodes or the one or more electrodes ofthe second plurality of electrodes may be based on the selection ofangles that are orthogonal relative to pairs of cathode electrodes andanode electrodes that are orthogonal to each other and a temperatureassociated deactivation state of one or more electrodes.

In some instances, selectively deactivating the one or more electrodesof the first plurality of electrodes or the one or more electrodes ofthe second plurality of electrodes may be based on the selection ofangles that are most distant from previous angles used within a currentduty cycle.

In some instances, selectively deactivating the one or more electrodesof the first plurality of electrodes or the one or more electrodes ofthe second plurality of electrodes may be based on a weighted product oftemperature multiplied by a function of the angle between thetemperature difference.

In view of the described apparatuses, systems, and methods andvariations thereof, hereinbelow are described certain more particularlydescribed embodiments of the invention. These particularly recitedembodiments should not however be interpreted to have any limitingeffect on any different claims containing different or more generalteachings described herein, or that the “particular” embodiments aresomehow limited in some way other than the inherent meanings of thelanguage literally used therein.

Embodiment 1: A method comprising: causing cyclical application of afirst electric field via a first transducer array in a first directionand a second electric field via a second transducer array in a seconddirection, opposite the first direction, wherein the first transducerarray comprises a first plurality of electrodes and the secondtransducer array comprises a second plurality of electrodes, and duringthe cyclical application, deactivating, based on a temperatureassociated with the one or more electrodes of the first plurality ofelectrodes or one or more electrodes of the second plurality ofelectrodes satisfying a threshold, the one or more electrodes of thefirst plurality of electrodes or the one or more electrodes of thesecond plurality of electrodes, activating, based on a temperatureassociated with the deactivated one or more electrodes of the firstplurality of electrodes or the deactivated one or more electrodes of thesecond plurality of electrodes no longer satisfying the threshold, thedeactivated one or more electrodes of the first plurality of electrodesor the deactivated one or more electrodes of the second plurality ofelectrodes.

Embodiment 2: The embodiment as in any one of the preceding embodimentswherein the first electric field and the second electric field areapplied with a frequency between 50 and 500 kHz and an electric fieldstrength of at least 1 V/cm to a tumor.

Embodiment 3: The embodiment as in any one of the preceding embodiments,wherein cyclical application comprises applying the first electric fieldapplied for between 20 and 500 ms in the first direction and the secondelectric field for between 20 and 500 ms in the second direction duringeach cycle.

Embodiment 4: The embodiment as in any one of the preceding embodimentsfurther comprising determining that the temperature associated with theone or more electrodes of the first plurality of electrodes or the oneor more electrodes of the second plurality of electrodes satisfies thethreshold.

Embodiment 5: The embodiment as in any one of the preceding embodimentsfurther comprising determining that the temperature associated with thedeactivated one or more electrodes of the first plurality of electrodesor the deactivated one or more electrodes of the second plurality ofelectrodes no longer satisfies the threshold.

Embodiment 6: The embodiment as in any one of the preceding embodimentsfurther comprising during the cyclical application, selectivelydeactivating, one or more electrodes of the first plurality ofelectrodes or one or more electrodes of the second plurality ofelectrodes, to adjust an angle at which the first electric field or thesecond electric field is applied to the region of interest.

Embodiment 7: The embodiment as in any one of the preceding embodiments,wherein selectively deactivating is based on a random selection ofangles at an optimal duty cycle.

Embodiment 8: The embodiment as in any one of the embodiments 1-6,wherein selectively deactivating is based on a random selection ofangles at a temperature-limited duty cycle.

Embodiment 9: The embodiment as in any one of the embodiments 1-6,wherein selectively deactivating is based on selection of angles thatare one or more of: most distant from previous angles used within acurrent duty cycle, and orthogonal relative to a geometric center of theregion of interest.

Embodiment 10: The embodiment as in any one of the embodiments 1-6,wherein selectively deactivating is based on selection of angles thatare one or more of: most distant from previous angles used within acurrent duty cycle, and orthogonal relative to pairs of cathodeelectrodes and anode electrodes that are orthogonal to each other.

Embodiment 11: A method comprising: causing cyclical application of afirst electric field via a first transducer array in a first directionand a second electric field via a second transducer array in a seconddirection, opposite the first direction, to a region of interest,wherein the first transducer array comprises a first plurality ofelectrodes and the second transducer array comprises a second pluralityof electrodes, and during the cyclical application, selectivelydeactivating, one or more electrodes of the first plurality ofelectrodes or one or more electrodes of the second plurality ofelectrodes, to adjust an angle at which the first electric field or thesecond electric field is applied to the region of interest.

Embodiment 12: The embodiment as in the embodiment 11, whereinselectively deactivating is based on a random selection of angles at anoptimal duty cycle.

Embodiment 13: The embodiment as in the embodiment 11, whereinselectively deactivating is based on a random selection of angles at atemperature-limited duty cycle.

Embodiment 14: The embodiment as in the embodiment 11, whereinselectively deactivating is based on selection of angles that are one ormore of: most distant from previous angles used within a current dutycycle, and orthogonal relative to a geometric center of the region ofinterest.

Embodiment 15: The embodiment as in the embodiment 11, whereinselectively deactivating is based on selection of angles that are one ormore of: most distant from previous angles used within a current dutycycle, and orthogonal relative to pairs of cathode electrodes and anodeelectrodes that are orthogonal to each other.

Embodiment 16: The embodiment as in the embodiment 11, wherein duringthe cyclical application, the method further comprises: deactivating,based on a temperature associated with the one or more electrodes of thefirst plurality of electrodes or the one or more electrodes of thesecond plurality of electrodes satisfying a threshold, the one or moreelectrodes of the first plurality of electrodes or the one or moreelectrodes of the second plurality of electrodes, and activating, basedon a temperature associated with the deactivated one or more electrodesof the first plurality of electrodes or the deactivated one or moreelectrodes of the second plurality of electrodes no longer satisfyingthe threshold, the deactivated one or more electrodes of the firstplurality of electrodes or the deactivated one or more electrodes of thesecond plurality of electrodes.

Embodiment 17: The embodiment as in the embodiment 16, whereinselectively deactivating is based on a random selection of angles at anoptimal duty cycle and a temperature associated deactivation state ofone or more electrodes.

Embodiment 18: The embodiment as in the embodiment 16, whereinselectively deactivating is based on a random selection of angles at atemperature-limited duty cycle and a temperature associated deactivationstate of one or more electrodes.

Embodiment 19: The embodiment as in the embodiment 16, whereinselectively deactivating is based on selection of angles that are one ormore of: most distant from previous angles used within a current dutycycle, and orthogonal relative to a geometric center of the region ofinterest and a temperature associated deactivation state of one or moreelectrodes.

Embodiment 20: The embodiment as in the embodiment 16, whereinselectively deactivating is based on selection of angles that are one ormore of: most distant from previous angles used within a current dutycycle, and orthogonal relative to pairs of cathode electrodes and anodeelectrodes that are orthogonal to each other and a temperatureassociated deactivation state of one or more electrodes.

Embodiment 21: The embodiment as in the embodiment 16, whereinselectively deactivating is based on a weighted product of temperaturemultiplied by a function of the angle between the difference intemperature.

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is in no way intendedthat an order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; the number or typeof embodiments described in the specification.

While the methods and systems have been described in connection withpreferred embodiments and specific examples, it is not intended that thescope be limited to the particular embodiments set forth, as theembodiments herein are intended in all respects to be illustrativerather than restrictive.

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is in no way intendedthat an order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; the number or typeof embodiments described in the specification.

It will be apparent to those skilled in the art that variousmodifications and variations can be made without departing from thescope or spirit. Other embodiments will be apparent to those skilled inthe art from consideration of the specification and practice disclosedherein. It is intended that the specification and examples be consideredas exemplary only, with a true scope and spirit being indicated by thefollowing claims.

What is claimed is:
 1. A method comprising: causing cyclical applicationof a first electric field via a first transducer array in a firstdirection and a second electric field via a second transducer array in asecond direction, opposite the first direction, wherein the firsttransducer array comprises a first plurality of electrodes and thesecond transducer array comprises a second plurality of electrodes; andduring the cyclical application, deactivating, based on a temperatureassociated with one or more electrodes of the first plurality ofelectrodes or one or more electrodes of the second plurality ofelectrodes satisfying a threshold, the one or more electrodes of thefirst plurality of electrodes or the one or more electrodes of thesecond plurality of electrodes, activating, based on a temperatureassociated with the deactivated one or more electrodes of the firstplurality of electrodes or the deactivated one or more electrodes of thesecond plurality of electrodes no longer satisfying the threshold, thedeactivated one or more electrodes of the first plurality of electrodesor the deactivated one or more electrodes of the second plurality ofelectrodes.
 2. The method of claim 1, wherein the first electric fieldand the second electric field are applied with a frequency between 50and 500 kHz and an electric field strength of at least 1 V/cm to atumor.
 3. The method of claim 1, wherein the cyclical applicationcomprises applying the first electric field for between 20 and 500 ms inthe first direction and the second electric field for between 20 and 500ms in the second direction during each cycle.
 4. The method of claim 1,further comprising determining that the temperature associated with theone or more electrodes of the first plurality of electrodes or the oneor more electrodes of the second plurality of electrodes satisfies thethreshold.
 5. The method of claim 1, further comprising determining thatthe temperature associated with the deactivated one or more electrodesof the first plurality of electrodes or the deactivated one or moreelectrodes of the second plurality of electrodes no longer satisfies thethreshold.
 6. The method of claim 1, further comprising during thecyclical application, selectively deactivating, the one or moreelectrodes of the first plurality of electrodes or the one or moreelectrodes of the second plurality of electrodes, to adjust an angle atwhich the first electric field or the second electric field is appliedto the region of interest.
 7. The method of claim 6, wherein selectivelydeactivating is based on a random selection of angles at an optimal dutycycle.
 8. The method of claim 6, wherein selectively deactivating isbased on a random selection of angles at a temperature-limited dutycycle.
 9. The method of claim 6, wherein selectively deactivating isbased on a selection of angles that are one or more of: most distantfrom previous angles used within a current duty cycle, and orthogonalrelative to a geometric center of the region of interest.
 10. The methodof claim 6, wherein selectively deactivating is based on a selection ofangles that are one or more of: most distant from previous angles usedwithin a current duty cycle, and orthogonal relative to pairs of cathodeelectrodes and anode electrodes that are orthogonal to each other.
 11. Amethod comprising: causing cyclical application of a first electricfield via a first transducer array in a first direction and a secondelectric field via a second transducer array in a second direction,opposite the first direction, to a region of interest, wherein the firsttransducer array comprises a first plurality of electrodes and thesecond transducer array comprises a second plurality of electrodes; andduring the cyclical application, selectively deactivating, one or moreelectrodes of the first plurality of electrodes or one or moreelectrodes of the second plurality of electrodes, to adjust an angle atwhich the first electric field or the second electric field is appliedto the region of interest.
 12. The method of claim 11, whereinselectively deactivating is based on a random selection of angles at anoptimal duty cycle.
 13. The method of claim 11, wherein selectivelydeactivating is based on a random selection of angles at atemperature-limited duty cycle.
 14. The method of claim 11, whereinselectively deactivating is based on selection of angles that are one ormore of: most distant from previous angles used within a current dutycycle, and orthogonal relative to a geometric center of the region ofinterest.
 15. The method of claim 11, wherein selectively deactivatingis based on selection of angles that are one or more of: most distantfrom previous angles used within a current duty cycle, and orthogonalrelative to pairs of cathode electrodes and anode electrodes that areorthogonal to each other.
 16. The method of claim 11, wherein during thecyclical application, the method further comprises: deactivating, basedon a temperature associated with the one or more electrodes of the firstplurality of electrodes or the one or more electrodes of the secondplurality of electrodes satisfying a threshold, the one or moreelectrodes of the first plurality of electrodes or the one or moreelectrodes of the second plurality of electrodes; and activating, basedon a temperature associated with the deactivated one or more electrodesof the first plurality of electrodes or the deactivated one or moreelectrodes of the second plurality of electrodes no longer satisfyingthe threshold, the deactivated one or more electrodes of the firstplurality of electrodes or the deactivated one or more electrodes of thesecond plurality of electrodes.
 17. The method of claim 16, whereinselectively deactivating is based on one or more of: a random selectionof angles at an optimal duty cycle and a temperature associateddeactivation state of one or more electrodes, and a random selection ofangles at a temperature-limited duty cycle and a temperature associateddeactivation state of one or more electrodes.
 18. The method of claim16, wherein selectively deactivating is based on selection of anglesthat are one or more of: most distant from previous angles used within acurrent duty cycle, and orthogonal relative to a geometric center of theregion of interest and a temperature associated deactivation state ofone or more electrodes.
 19. The method of claim 16, wherein selectivelydeactivating is based on selection of angles that are one or more of:most distant from previous angles used within a current duty cycle, andorthogonal relative to pairs of cathode electrodes and anode electrodesthat are orthogonal to each other and a temperature associateddeactivation state of one or more electrodes.
 20. The method of claim11, wherein selectively deactivating is based on a weighted product oftemperature multiplied by a function of an angle between a difference intemperature between two transducers and an angle between lines drawnfrom their centers to the geometric center of the estimated targetlocation.